20
10
0
发病年龄
Figure 63–1 The length of the CAG repeat and age of onset
in spinocerebellar ataxia (SCA) are inversely correlated.
The longer the CAG tract, the earlier is the onset for a given
disease. Specific repeat lengths, however, have different
results depending on the host protein. For example, a 52-repeat
of CAG causes juvenile onset of symptoms in spinocerebel-
lar ataxia type 2 (SCA2), adult onset in spinocerebellar ataxia
type 1 (SCA1), and no disease in spinocerebellar ataxia type 3
(SCA3).
• In SCA17, the affected gene product is the TATA box-
binding protein, an essential transcription factor.
• Atrophin-1, the disease-causing protein in DRPLA,
is thought to be a corepressor based on functional
studies of its probable ortholog in Drosophila.
Despite these differences, some pathogenetic
mechanisms may be common to the polyglutamine
diseases, as discussed later in this chapter.
CAG repeats in coding regions are not the only
dynamic mutations occurring in the SCAs (Table 63–2).
SCA8 involves expansion of both a CAG tract and its
complementary CTG repeat on the opposite strand in
the 3′ untranslated region of a transcribed RNA with
no open reading frame. The mutation responsible for
SCA12 is a CAG repeat, but it occurs in a noncoding
region 5′ upstream of a brain-specific regulatory sub-
unit of the protein phosphatase 2A. SCA10 is caused
by massive expansion of a pentanucleotide (ATTCT)
repeat in the intron of a novel gene.
So far, a total of 33 SCAs have been identified. For
the SCAs whose underlying pathogenesis is better
understood, the most promising therapeutic approach
seems to be to reduce the levels of the disease-driving
protein. In the SCA7 mouse model, reducing the
amount of both mutant and wild-type ATXN7 by RNA
interference greatly improves the behavioral and path-
ological signs of disease. Likewise, in both Drosophila
and mouse models of SCA1, genetic or pharmaco-
logical downregulation of several components of the
RAS-MAPK-MSK1 pathway decreases ATXN1 levels
and suppresses neurodegeneration.
Parkinson Disease Is a Common
Degenerative Disorder of the Elderly
Parkinson disease, one of the more common neuro-
degenerative disorders, affects approximately 3% of the
population older than age 65 years. Patients with
Parkinson disease suffer from a resting tremor,
bradykinesia, rigidity, and impairment in their abil-
ity to initiate and sustain movements. Affected indi-
viduals walk with a distinctive shuffling gait, and
their balance is often precarious. Spontaneous facial
movements are greatly diminished, creating a mask-like,
expressionless appearance. The pathological hallmarks
of Parkinson disease are the progressive loss of dopa-
minergic neurons, mainly in the substantia nigra pars
compacta (Chapter 38), and the accumulation of pro-
teinaceous aggregates termed Lewy bodies and Lewy
neurites throughout the brain.
Although most cases of Parkinson disease are spo-
radic, studies of rare familial cases, which can be either
autosomal dominant or recessive, have provided
insight into the pathophysiology of this disorder and
revealed novel risk factors for disease. To date, several
genetic loci have been mapped (designated PARK1–
PARK22), and the genes for all but four of these loci
(PARK3, PARK10, PARK12, and PARK16) have been
identified (Table 63–3). Of these mapped loci, the most
studied and characterized are PARK1/4, PARK2, PARK6,
and PARK7. Here, we focus on how the genetic basis of
some forms of Parkinson disease provides insight into
sporadic Parkinson disease.
Parkinson disease type 1/4 (4q2-22) is the locus for
the dominantly inherited Parkinson disease caused by
mutations in the gene SNCA encoding for α-synuclein.
(As with Machado-Joseph disease and SCA3, Park1
and Park4 were initially thought to be two distinct var-
iants.) Variants in the SNCA locus have been associated
with increased risk of sporadic Parkinson disease, and
several mutations in SNCA alter the conformation of
the membrane-bound portion of the α-synuclein pro-
tein and cause it to aggregate. Duplications and trip-
lications of SNCA have also been identified as causes
of autosomal dominant Parkinson disease, indicating
that elevated levels of even wild-type α-synuclein can
cause disease. Patients with SNCA duplication have
a disease course that resembles sporadic cases, but
patients with triplication manifest an earlier-onset,
more rapidly progressing disease with atypical fea-
tures such as dementia and hallucinations.
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